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PMID: 38925119 Published · ppublish English Journal Article

Splicing-specific transcriptome-wide association uncovers genetic mechanisms for schizophrenia.

American journal of human genetics ·Vol. 111 ·No. 8 ·2024-08-08 ·Pages 1573-1587

Hervoso JL, Amoah K, Dodson J, Choudhury M, Bhattacharya A, Quinones-Valdez G, Pasaniuc B, Xiao X

Abstract

Recent studies have highlighted the essential role of RNA splicing, a key mechanism of alternative RNA processing, in establishing connections between genetic variations and disease. Genetic loci influencing RNA splicing variations show considerable influence on complex traits, possibly surpassing those affecting total gene expression. Dysregulated RNA splicing has emerged as a major potential contributor to neurological and psychiatric disorders, likely due to the exceptionally high prevalence of alternatively spliced genes in the human brain. Nevertheless, establishing direct associations between genetically altered splicing and complex traits has remained an enduring challenge. We introduce Spliced-Transcriptome-Wide Associations (SpliTWAS) to integrate alternative splicing information with genome-wide association studies to pinpoint genes linked to traits through exon splicing events. We applied SpliTWAS to two schizophrenia (SCZ) RNA-sequencing datasets, BrainGVEX and CommonMind, revealing 137 and 88 trait-associated exons (in 84 and 67 genes), respectively. Enriched biological functions in the associated gene sets converged on neuronal function and development, immune cell activation, and cellular transport, which are highly relevant to SCZ. SpliTWAS variants impacted RNA-binding protein binding sites, revealing potential disruption of RNA-protein interactions affecting splicing. We extended the probabilistic fine-mapping method FOCUS to the exon level, identifying 36 genes and 48 exons as putatively causal for SCZ. We highlight VPS45 and APOPT1, where splicing of specific exons was associated with disease risk, eluding detection by conventional gene expression analysis. Collectively, this study supports the substantial role of alternative splicing in shaping the genetic basis of SCZ, providing a valuable approach for future investigations in this area.

Keywords
RNA binding proteins TWAS alternative RNA splicing fine mapping genetic variations neurological disorders
MeSH Terms
Humans Schizophrenia/genetics Genome-Wide Association Study Transcriptome Alternative Splicing/genetics Exons/genetics Genetic Predisposition to Disease RNA Splicing/genetics Polymorphism, Single Nucleotide
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
Hervoso Jonatan L
Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Amoah Kofi
Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Dodson Jack
Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Choudhury Mudra
Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Bhattacharya Arjun
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Quinones-Valdez Giovanni
Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
Pasaniuc Bogdan
Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Computational Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: [email protected].
Xiao Xinshu
Bioinformatics Interdepartmental Program, University of California, Los Angeles, Los Angeles, CA 90095, USA; Department of Integrative Biology and Physiology, University of California, Los Angeles, Los Angeles, CA 90095, USA. Electronic address: [email protected].
Conflict of Interest

Declaration of interests The authors declare no competing interests.

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Article Info
Journal
American journal of human genetics
Abbr.
Am J Hum Genet
ISSN
1537-6605
DOI
10.1016/j.ajhg.2024.06.001
Email
[email protected]
[email protected]
Published
2024-08-08
Epub
2024-00-25
Pages
1573-1587
Language
English
Region
United States
NLM ID
0370475
PMCID
PMC11339621
Subset
IM
Grants
NIA NIH HHS · R01 AG056476 · United States
NIMH NIH HHS · R01 MH123177 · United States
NHLBI NIH HHS · T32 HL139450 · United States
NLM NIH HHS · T32 LM012424 · United States
External Links
PubMed source DOI: 10.1016/j.ajhg.2024.06.001 PMC Full Text View journal details
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